Control of microorganisms with o,n-diphenylcarbamic acid esters

ABSTRACT

Certain O,N-diphenyl-carbamic acid esters in which one phenyl moiety is substituted in the 2-position by a halogenated phenoxy radical are disclosed as microbicidally active compounds. A method for controlling microorganisms with the aid of such compounds and compositions containing them are also described.

United States Patent [191 Traber et al.

[ Nov. 5, 1974 CONTROL OF MICROORGANISMS WITH O,N-DIPHENYLCARBAMIC ACIDESTERS Inventors: Walter Traber, Riehen; Heinz Hambock, Binningen; AntonGeorg Weiss, Benken, all of Switzerland Assignee: Ciba-GeigyCorporation, Ardsley,

Filed: Jan. 2, 1973 Appl. No.: 320,388

Related US. Application Data Division of Ser. No. 5,954, Jan. 26, 1970,Pat. No. 3,721,699.

US. Cl 424/300, 260/455 A, 260/471 C,

106/15 AF Int. Cl. A0ln 9/12, A0ln 9/20 Field of Search 424/300 [56]References Cited UNITED STATES PATENTS 3,609,177 9/1971 Traber et al.424/300 Primary ExaminerVincent D. Turner Attorney, Agent, orFirm-Joseph G. Kolodny; Edward McC. Roberts; Prabodh I. Almaula [57]ABSTRACT 23 Claims, No Drawings CONTROL OF MICROORGANISMS WITHO,N-DIPHENYLCARBAMIC ACID ESTERS This is a division of application Ser.No. 5,954, filed on Jan. 26, 1970, now US. Pat. No. 3,721,699.

The present invention concerns new O,N-diphenylcarbamic acid esters,process for the production of these compounds as well as compositionsand methods for the control of microorganisms employing the new carbamicacid esters.

The new O,N-diphenyl-carbamic acid esters (carbanilic acid-phenylesters) correspond to the Formula I In this formula:

R represents a phenoxy radical substituted by at least one and at mostthree identical or differing halogen atoms,

of the symbols R R and R at least one represents chloride or bromine,the others each independently represent hydrogen, chlorine or bromine,

R and R each independently represent hydrogen,

halogen, lower alkyl, lower alkoxy, lower halogenalkyl, nitro orhydroxy,

R represents hydrogen, halogen, lower alkyl, lower alkoxy, dialkylamino,hydroxy, and

X represents oxygen or sulfur.

In Formula 1, R is in particular one of the following halogenatedphenoxy radicals: 4-chlorophenoxy, 4- bromophenoxy, 2,4-dichlorophenoxy,2,4- dibromophenoxy, 2,4,5-trichlorophenoxy.

Lower alkyl and lower alkoxy radicals R to R have from 1 to 4 carbonatoms. As halogenalkyl, trifluormethyl is preferred. The alkylsubstituents in a dialkylamino group are radicals having 1 to 4 carbonatoms in particular the methyl radical. By halogen represented by R Rand/or R is meant fluorine, chlorine, bromine and iodine, especiallyhowever, fluorine, chlorine and/or bromine.

The new, O,N-diphenyl-carbamic acid esters are obtained according to theinvention, either a. by converting a phenol of the Formula 11 as such orin the Form of one of its alkali metal or alkaline earth metal salts,with phosgene or thiophosgene into an acid chloride of the Formula [II(III) and reacting this with an aniline of the Formula IV In theFormulas I to V, the symbols R to R and X have the meanings given forFormula I.

The process according to the invention is preferably carried out in thepresence of a solvent or diluting agent and of an acid-binding agent(proton acceptor).

Examples of suitable solvents or diluting agents are: hydrocarbons, suchas toluene, benzene or ligroine, halogenated hydrocarbons, such aschloroform, carbon tetrachloride or chlorobenzene, amides such asdimethylformamide, ethers and ether-like compounds such astetrahydrofuran, dioxan or diisopropylether, ketones such as acetone ormethyl-ethylketone. Acid-binding agents are preferably organic bases,e.g., tertiary amines such as pyridine, triethylamine etc., inorganicbases such as the hydroxides and carbonates of alkali metals andalkaline earth metals.

In the following examples, the production of some of thediphenyl-carbamic acid esters of Formula I is described. Thetemperatures are given in degrees centigrade.

EXAMPLE 1 a. About g of phosgene are introduced at 0 into 500 ml oftoluene. To this solution there is added dropwise at 0 to 5, a solutionof 289.5 g of 4.2',4- trichloro-2-hydroxy-diphenyl ether in 700 ml oftoluene, and 100 g more of phosgene are introduced. While stirring, asolution of 111.3 g of triethyl amine in 200 ml of toluene is then addedto the reaction mixture. After standing for several hours at roomtemperature, the excess phosgene is removed, thetriethylamine-hydrochloride is separated, and the solvent is removedfrom the filtrate. The residue is fractionated, the O-[2-(2',4'-dichlorophenoxy)-5-chlorophenyl]-carbonyl chloride boils at 180-184 and0.5 Torr.

b. 35.2 g of O-[2-(2,4-dichlorophenoxy)-5-chlorophenyl]-carbonylchloride, dissolved in 300 ml of acetone, are treated dropwise at 15 to20 with a solution of 32.4 g of 3,5-dichloraniline in ml of acetone.

The reaction mixture is then allowed to stand for 3 hours at roomtemperature, poured onto water, and the precipitate which separates outafter several hours is removed by filtration. After recrystallizingseveral times from cyclohexane and benzene/petroleum ether,N-(3,5-dichlorophenyl)-carbamic acid-O-[2-(2',4'-

dichlorophenoxy)--chloropheny1]-ester melting point of 132134 isobtained.

EXAMPLE 2 a. A solution of 150 g of thiophosgene in 400 ml of chloroformis added to a solution of 289.5 g of 2',4'-dichloro-2-hydroxy-4-chloro-diphenyl ether in 400 ml of chloroform, andcooled to 5. While stirring vigorously, an aqueous sodium hydroxidesolution, 50 g of sodium hydroxide dissolved in 790 ml of water, is thenadded dropwise in such a manner that the temperature does not exceed Thereaction mixture is then stirred for 2 hours at room temperature, theorganic phase is separated, washed with water, and dried over sodiumsulfate. After the solvent is removed by distillation, the residue isfractionated in vacuum. The 2-(2,4'-dichlorophenoxy)-5-chlorophenyl-thiocarbonyl chloride boils at175-184 0.05 Torr. (n =1.6275).

having a b. 'A solution of 24.2 g of 3,5-dimethylaniline in 150 ml ofbenzene is added dropwise at 5 during 1.5 hours to a solution of 36 g ofO-[2-(2,4-dichlorophenoxy)- S-chlorophenyl]-thiocarbonylchloride in 150ml of benzene. The mixture is then stirred for 12 hours at roomtemperature, shaken out with water, and dried over sodium sulfate. Afterthe solvent has been removed by distillation, the residue of theO-[2-(2,4- dichlorophenoxy)-5-chlorophenyl]-thiocarbamic acid-N-(3,S-dimethylphenyl)-ester, recrystallized from benzene/petroleumether, has a melting point of 102104.

EXAMPLE 3 A solution of 19.8 g of 3-bromo-phenyl-isocyanate in 50 ml ofligroin is added dropwise to a suspension of 30 g of4'-bromo-4-ch1oro-2-hydroxy-diphenyl ether in 100 ml of ligroin. Afterthe addition of 2 ml of triethylamine, the mixture is refluxed for 1hour and then cooled. The precipitate which separates is separated, andrecrystallized from benzene/petroleum ether (1:1). TheN-(3-bromopheny1)-carbamic acid-O-[2-(4-bromophenoxy)-5-chlorophenyl]-ester has a melting point of 116.

The following O,N-diphenyl-carbamic acid esters are prepared from thecorrespondingly substituted 2- hydroxydiphenyl ethers or2-phenoxyphenyl-carbony1 chlorides in accordance with the proceduresdescribed in the foregoing examples.

TABLE l-Continued Compound Melting PointN-(3-trif1uoromethyl-4-chlorophenyl)- thiocarbamic acid-0-[2-(4-chlorophenoxy)-5-ch1orophenyllesterN-(3-trifluor0methy1-6-chlorophenyl)- thiocarbamic acid-O-[2-(4'-chlorophenoxy)-5-chlorophenyl]-ester N-(4-methylphenyl)-carbamicacid-O-[2-(4'- chlorophenoxy)-5-ch1orophenyl]-esterN-(4-methylphenyl)-thiocarbamic acid-0-[2-(4'-ch1orophenoxy)-5-ch1orophenyl]-ester N-(Z-methylphenyl)-thiocarbamicacid-0-[2- (4-chlorophenoxy)-5-chlorophenyl]-esterN-(3,5-dimethylpheny1)-thiocarbamic acid-0-[2-(4'-chlorophenoxy)-5-ch1orophenyl]- esterN-(3-methoxypheny1)-carbamic acid-0-[2- (4 '-chlorophenoxy)-5-ch1orophenyl l-ester N-(3-methoxypheny1)-thiocarbamic acid-0-[2-(4-chlorophenoxy)-5-ch1orophenyl]- ester N-(4-chlorophenyl)-carbamicacid-0-[2-(4 bromophenoxy)-5-chlorophenyl]-esterN-(3-bromophenyl)-carbamic acid-O-[2-(4-bromophenoxy)5-chlorophenyll-ester N-(3,4-dichloropheny1)-carbamicacid-O-[Z- (4'-bromophenoxy)-5-chlorophenyl]-esterN-(3-trifluoromethylphenyl)-carbamic acid-0-[2-(4'-bromophenoxy)-5-chloropheny1]- esterN-(Z-methylphcnyl)-carbamic acid-0-[2-(4-bromophenoxy)-5-chloropheny1]-ester N-(3-chlorophenyl)-carbamicacid-0-[2-(4 chlorophenoxy)-5-bromophenyl]-esterN-(2,4-dich1orophenyl)-carbamic acid-0-[ 2-(4-ch1orophenoxy)-5-bromophenyll-esterN-(3-trifluoromethy1-4-ch1orophenyl)- carbamicacid-0-[2-(4"ch1orophenoxy)-5- bromophenyll-ester N-(3,5)-bis-(trifluoromethylphenyl)- carbamic acid-0-[2-(4chlorophenoxy)-5bromophenyll-ester N-(3-methoxyphenyl)-carbamic acid-O-[Z-(4-chlorophenoxy)-5-bromophenyl]-ester N-(3,4-dichloropheny1)-carbamicacid-0-[2- (4'-br0mophenoxy)-5-bromophenyl]-esterN(3-trifluoromethylphenyl)-carbamic acid-0-[2-(4'-bromophenoxy)-5-bromophenyl]- ester N-(3-methylphenyl)-carbamicacid-0-[2-(4- bromophenoxy )-5-bromophenyl]-esterN-(4-methoxyphenyl)-carbamic acid-0-[2-(4-bromophenoxy)-5-bromopheny1]-ester N-(4-chlorophenyl)-carbamicacid-0-[2-(4'- chlorophenoxy)-4-bromo-5-chlorophenyl]- esterN-(3-ch1orophenyl)-carbamic acid-0-[2-(4chlorophenoxy)-4-bromo-5-chlorophenyllester N-(3-bromophenyl)-carbamicacid-0-[2-(4 chlorophenoxy)-4-bromo-5-chlorophenyl1- esterN-(4-bromophenyl)-thiocarbamic acid-0-[2- (4'-ch1orophenoxy)-4-bromo-5-chlorophenyll-ester N-(3,4-dichlorophenyl)-carbamic acid-O-[2-(4'-chlorophenoxy)-4-bromo-5- chloro henyl]-esterN-(3drifliroromethyl-4-chlorophenyl)- carbamicacid-0-[2-(4'-chlorophenoxy )-4- bromo-S-chlorophenyl[-esterN-(3-trifluoromethylphenyl)-carbamic acid-0-[2-(4'-ch1orophenoxy)-4-bromo-5- chlorophenyll-esterN-(3-trifluoromethy1phenyl)-thiocarbamicacid-O-l2-(4'-ch1orophenoxy)4-bromo-5- chlorophenyH-esterN-(4-methylphenyl)-carbamic acid-0-[2-(4'-chlorophenoxy)-4-bromo-5-chlorophenyl1 TABLE l-Continued CompoundMelting Point The new carbamic acid esters of Formula 1 are colorlesssolids which can be purified by recrystallization. They are onlyslightly toxic for warm-blooded animals and do not irritate the skin inthe concentrations normal for use. The advantage of the new carbamicacid esters to be colorless or to have only aslight intrinsic colormakes possible their use in many areas where strongly colored compoundswould be unsuitable.

The new diphenyl-carbamic acid esters of Formula I have very goodbacterostatic and bactericidal effects against gram-positive andgram-negative bacteria, for example: Staphylococcus aureus SG 51 lStaphylococcus aureus Smith, Staphylococcus lactis, in addition Bacillusmesentericus, Bacillus pumilus, Bacillus subtilis, Coli forms,Corynebacterium diphtheriae, Clostridium betulinum, Clostridiumbutyricum, Clostridium welchii, Clostridium tetani, Klebsiellpneumoniae, Alcaligenes faecalis, Sarcina spec., Salmonella pullorum,Salmonella typhi, Salmonella paratyphi A and B, Salmonella typhimu--rium, Salmonella enteritidis, Shigella dysenteriae, Shigellaflexneri,Brucella abortus, Proteus mirabilis, Achromobacter spec., Serratiamarcescens, Pasteurella pseudotuberculosis. The compounds of Formula Ialso have very good activity against fungi, for example against thefollowing fungi: Aspergillus spec., e.g., Aspergillus niger, Aspergillusflavus, Aspergillus fumigatus, Candida spec., e.g., Candida albicans,Candida tropicalis, Pencillium spec., for example Penicillium italicum,Penicillium chrysogenum, Epidermophyton spec., Trichophyton spec.,Ctenomyces spec., Keratinomyces spec., Blastomyces spec., Microsporumspec., Cryptococcus neolflormms l-2 .T PlQR l W E u fll ff F9 2Aerostalagmus Cinnabarinus, Fusarium oxysporum, cellulose-degradingfungi, wood fimgi, etc.

O-phenoxyphenyl-N-trifluoromethylphenyl carbamic acid esters which areunsubstituted in the phenoxy group are embraced by the Dutch patentapplication open to public inspection No. 6,606,753 as anthelminths, nothowever being described. These compounds however have no, or only veryweak microbicidal properties. In addition a series of Ohalogenophenyl-N-phenyl-carbamic acid esters or O-phenyl-N-halogenophenyl-carbamic acid esters are described as herbicidesand for use in'plant protection. These compounds are, however, due totheir lack of effect or lack of broad enough range of action,unsuitable, especially for the control of pathogenic microorganisms, forexample of the urinal tract and intestines of warm-blooded animals.

to determine the bacteriostatic and fungistatic action of the compoundsof Formula I, the following microorganisms were used:

A. Bacteria Escherichia coli, Bacillus pumilus, Sarcina ureae, Bacillussubtilis, Sarcina lutea, Streptococcus faecalis, Staph. saproph., Staph.aureus, Corynebact. diphtheroides l7, Brevibact. ammoniagenes,Salmonella pullorum, Proteus vulgaris HXL, Protecus vulgaris ox l9,Proteus mirabilis;

B. Fungi la. Aspergillus niger, Penicillium italicum, Fusariumoxysporum, Candida albicans, Stemphylium botryosum,

lb. cellulose-degraders: Chaetomium globosum, Trichoderma viride,Metarrhizium glutinossum, Stachybotrys atra,

2. yeast: Saccharomyces cerevisiae, Torula utilis, Monilia nigra,

3. facultative Dermatophytes: Trichophyton gypseum, Ctenomyces spec.,Keratinomyces ajelloi, Epidermophyton floccosum,

4. ubiquitous Saprophytes: Rhizopus nigricans, Paecilomyces van'oti,Penicillium citrinum, Aspergillus myme, Aspergillus clavatus,Aspergillus flavus.

5. Fungi imperfecti: Scopulariopsis brevicaulis, Altemaria tenuis,Aerostalagmus cinnabarinus, 6. Coniophora cerebella, poria vaporaria,Poria incarnata,

7. Polystictus versicolor, Daedelea quericina, Lencites abietinamLentinus lepideus,

8. parasites: Fomes annosus 9. blue stain: Scoplularia phycomyces,Pullularia pullulans.

C. Method The lowest growth-inhibiting concentration for the variousmicroorganisms was determined by mixing the solution of active substancewith nutrient agar while still warm. The agar is then poured into platesand, after solidification, inoculated with the test germs.

In the following table are listed: the nutrient media used for thevarious organisms, the incubation temperature and incubation time, aswell as the concentration 91th? ast shstan ysesia.

Table} Continued Compound Asper- Asper- Peni- F usarium Candida Dermato-Rhisophus Pacciloryces Fungi Pullularia No. Gillus gillus cilliumoxyalbicans phylum nigricaruvariori imperfecti pullulans (Table 1) nigerniger italic-um sporum 47 30 1O 10 30 48 100 100 30 30 30 10 10 30 10 3049 30 100 30 10 30 10 30 50 30 10 30 10 30 10 10 100 10 30 51 30 100 3030 30 10 30 30 1030 30 52 100 100 30 30 30 10 10 30 10 30 53 30 30 10 330 10 30 54 10 30 30 30 10 30 30 10 30 55 100 30 30 30 30 10 30 30 30 3056 100 30 30 30 10 30 30 30 57 100 30 30 30 30 10 10 30 10 30 67 30 3O10 30 30 10 10 30 10 30 68 30 100 30 30 30 10 10 30 10-30 30 73 100 3030 30 30 10 10 30 10-30 30 74 100 30 30 30 30 10 30 30 10 30 75 30 30 1010 30 10 30 76 30 100 30 30 30 10 30 30 10-30 30 77 30 30 30 30 30 10 1030 10-30 30 78 100 30 30 30 30 10 30 30 10 30 91 100 30 10 10 10 30 1010 30 92 100 10 10 30 10 10 30 10 30 93 30 30 10 3O 10 10 30 10 30 94 3010 10 30 10 10 30 10 30 The bacteriostatic and fungistatic activity ofthe compounds according to the invention was further deter- Thefollowing microorganisms were used Test 1 a) Bacteria s h i a 9951993195, sm les t:

Bacteria: Escherichia coli, Salmonella pullorum, Proteus vulgaris HXL.

The nutrient media used for the various organisms, 30 the incubationtemperature and incubation time, as

Nutrient Incubation Organism Concentration of medium active substancetemp. time in ppm* a) Bacteria Nutrient-Agar 37 48 hrs. 30-10-3-11000-300-100 b) Fungi l. Nutrient-Agar 37 48 hrs. 100-30-10-3 1000-3002. Wort-Agar 28 5 days 100-30-10 (for yeasts) ppm: Part of activesubstance per 10 parts of agar.

cina ureae Staphylococcus aureus, Proteus vulgaris 45 As comparativesubstances were used the following compounds:

A N-(3-trifluoromethylphenyl)-carbamic acid-0-( 2-phenoxyphenyl )-esterB N-(3.S-bis-trifluoromethylphenyl)-carbamicacid-O-(2-phenoxypheneyl)-ester CN-(3-trifluoromethylphenyl)-thiocarbamic acid-O-( 2-phenoxyphenyl)-estergs Patent No 3,142,646).

b. Fungi: Aspergillus niger, Fusarium oxysporum, albicans, Saccharomyces(yeast), Torula utilis (yeast).

Candida Test 2 cerevisiae British Patent No.

In the following Table 4 are given the results of Test 1 and in Table 5those of Test 2. The figures indicate those concentrations, at which nogrowth can be determinated.

13 14 Table 4 I Egktflia Ftmgi Compound Staphyln- Bacillus SarcinaEscherichia Proteus Asper- Fusan'um Candida Saccharo ToruIa No. coccuspumilus ureac NCTC vulparis gillus oxysporum albicans myces utilis(Table l) aureus Fey 8195 niger cerevisae 5 3 10 1 10 100 10 30 100 10010 1 3 3 1 10 100 30 30 100 100 25 ,1 3 10 1 10 100 30 30 30 30 33 3 1 310 30 30 10 30 30 30 39 3 1 3 3 30 3o 30 30 30 30 57 1 3 1o 1 10 100 3030 100 30 81 1 1 3 1 10 30 10 30 30 30 84 1 3 10 1 10 30 10 30 30 30 1001 1 10 10 10 30 10 30 3o 30 A 100 100 1000 30 1000 1000 300 1000 10001000 B 100 100 1000 100 1000 1000 300 1000 1000 1000 c 100 100 1000 1001000 1000 300 1000 1000 1000 D 300 100 1000 100 1000 1000 300 300 10001000 Control 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 Tabletreated with optical brightening agents was rinsed in the bath describedunder (A). The cotton fabric was Compound Escherichia Proteus S 1mm Ellapunched into disks of 2.5 cm in diameter. These disks No. coli vulgarispullonum were placed each on one agar plate prepared according (Table 1)NCTC 8196 h b d to MacConkey, supra, t ere y using nutrmve agar an 3 110 nutritive agar containing 0.5 percent by weight of pog 1 tassiumtellurite depending on whether the tests are 46 28 2:8 performed withEscherichia coli or Staphylococcus au 51 1 10 10 reus SG 511. The agarplates (in Petri dishes) were 22 1 28 28 then incubated for 24 hours at37C. The growth on the E 300 300 300 agar plates was then evaluatedvisually. The results are F 300 30 compiled in Table 7 wherein G 300 300300 comm] 300 300 represents growth under the textile sample Thedisinfectant effect of the compounds according to the invention wasdetermined by means of the following tests A. Germ count in the rinsebath The third rinse bath containing the active substance to be testedwas inoculated with Staphylococcus aureus SG 511 and Escherichia coli.One ml of this bath was added to 20 ml nutritive agar prepared accordingto MacConkey [Difco Manual 9th Edition, (1953), page 131] when testingEscherichia coli and to 20 ml nutritive agar to which 0.5 percent byweight of potassium tellurite had been added when testing Staphylococcusaureus SG 511. The resultant mixture was put into Petri dishes whichwere incubated for 24 hours at 37C. The viable germ count per mil ofrinse bath was determined by counting the number of colonies formed onthe agar plates. The results are compiled in Table 6.

' 1 part active substance per I0 parts rinse bath B. Rinse bathdisinfection test fin d .9.tt ,.fab whishhaq n been represents no growthunder the textile sample 1 represents traces of growth under the textilesample.

Table 7 Escherichia coli Bacterium Staphylococcus aureus SG 51 1Concentration in m" 6,2

Compound No. (Table l) +++++I| l l I ll ++l l l I I l I ll ++++I l I l Ill ++++lllllll 1 part active substance per lo parts rinse bath overlaidon each ofthe Petri dishes containing the Bacto-Agar. Cotton fabricdisks treated according to (B) above were, after drying, each laid on aPetri dish, which was then incubated for 24 hours at 37C. Thereafter,the zone wherein all growth of the bacteria had been inhibited wereassessed in millimeters. The results obtained are given in Table 8,wherein signifies growth under the textile sample signifies no growthunder the textile sample i signifies traces of growth under the textilesample 15 Table 8 Bacterium Staphylococcus Escherichia aureus SG 5l lcoli Concentration in m 6,2 25 6,2 25

Compound No. (Table l) 3 9- ll- 6- l 7- l5- 6 l0- lO 1 l l3 9 46 8- ll 34- 5l 7 l0- 4 53 8- l l 3- 5- 55 l0- l3- 5- 6 E 0+ 0 0+ 0+ F 0+ 0: 0+ 0+G 0+ 0+ 0+ 0+ Control 0+ 0+ 0+ 0+ l part active substance per 10' partsrinse bath The diphenyl-carbamic acid esters of Formula I, producedaccording to the invention, have a broad and va iesraaseqtap on for theom ql 9t m swn. ganisms, especially of bacteria and fungi, and for theprotection of organic materials and objects against attack bymicroorganisms. Thus, they can be directly worked into the material tobe protected, for example into synthetic resin materials such aspolyamides and polyvinyl chloride,into baths for the treatment of paper,into thickeners for printing inks, consisting of starch or cellulosederivatives, into lacquers and paints, containing casein for example,into cellulose, into viscose spinning masses, into paper, into animalmucilages or oils, into polyvinyl alcohol based permanent sizing agents,into cosmetic articles, into ointments or powders. In addition they canbe added to preparation of inorganic or organic pigments for painters,plasticizers, etc. The new compounds are especially valuable for theprotection of textiles of all kinds, e.g., textiles based on celluloseand keratin material, since they are notably substantive to such fibermaterials.

In still other application forms, the carbamic acid esters of Formula Ican be employed dissolved in organic solvents, for example as so-calledsprays or as dry cleaners or to impregnate wood, the organic solventbeing preferably non-miscible with water, in particular petroleumfractions; but also water-miscible solvents such as lower alcohols, forexample methanol or ethanol, or ethylene glycol monomethyl or monoethylether are suitable.

In addition, they can be employed together with wetting or dispersingagents in the form of aqueous dispersions, for example for theprotection of substances which tend to rot such as for the protection ofleather, paper, etc.

Solutions or dispersions of the active substances, which can be employedfor the protection of these materials, preferably have a concentrationof active substance of at least 0.005 g/liter.

A preferred field of application of the diphenyl carbamic acid esters ofFormula I is the disinfection of washed goods and for the protection ofwashed goods against attack by microorganisms. For this purposeingagents, for example those based on synthetic resins or starch.

Suitable as wash goods which can be disinfected with rinse bathscontaining the compounds according to the invention are primarilyorganic fiber materials, namely that of natural origin such ascellulosic material, e.g., cotton; or polypeptide material, e.g., woolor silk; or synthetic fiber material such as that based on polyamide,polyacrylonitrile or polyester; or mixtures of the above fibers.

The carbamic acid esters according to the invention in theconcentrations given, impart to the bath as well as to the treated washgoods a broad and long-lasting disinfection against Staphylococcus andColi forms, which continues even after exposure of the active substanceor the goods treated therewith to light. They are distinguished by theirhigh stability to light on the goods treated therewith as well as bytheir high activity and broad range of action against gram-positive andgram-negative organisms. V p

The new carbamic acid esters are also very effective against thebacterial flora causing persiration odor, and for that reason andbecause of their slight toxicity, they are suitable as deodorants forlaundry or as additives for cosmetic agents such as ointments or creams.

Especially valuable is the use of the new carbamic acid esters ofFormula I produced according to the invention as active substances forthe healing of diseased conditions of the skin, the intestinal systemand the urinal tract of warm-blooded animals, which is possible due totheir excellent action against pathogenic bacteria and fungi, theirrelatively low toxicity, as well as the fact that they are largelyexcreted from the body in an unchanged, active form.

The antimicrobial compositions according to the invention contain atleast one diphenyl carbamic acid ester of Formula I as activeingredient, together with the usual pharmaceutical carriers. The type ofcarrier depends to a large extent on the intended use. Ointments,powders and tinctures are especially suitable for external application,for example for the disinfection of healthy skin as well as for thedisinfection of wounds and for the treatment of dermatoses andaffections of the mucous membranes which are caused by bacteria orfungi. The ointment bases can be anhydrous, e.g., they can consist ofmixtures of wool fat and vaseline, or they can consist of aqueousemulsions in which the active substance is suspended. Suitable carriersfor powders are, e.g., starches, such as rice starch, the bulk weight ofwhich, if desired, can be made lighter, e.g., by the addition of highlydispersed silicic acid, or heavier by the addition of talcum. Tincturescontain at least one diphenyl carbamic acid ester of Formula I inaqueous ethanol, in particular 45-75 percent ethanol, to which, ifdesired, 10-20 percent glycerin may be added. Solutions prepared fromthe usual solubility promoters such as, e.g., polyethylene glycol, aswell as optionally, from emulsifying agents, are used in particular forthe disinfection of healthy skin. The content of active ingredient inthe above forms for external application is preferably between 0.1 and 5percent.

Suitable for the disinfection of the mouth and throat are gargles, orconcentrates for the preparation thereof, in particular prepared fromalcoholic solutions containing about 1-5 percent of active substance towhich glycerin and/or flavorings can be added, and also lozenges, i.e.,solid dosage units, having a relatively high content of sugar or simlarsubstances and a relatively low content of active substance of about 0.220 percent, as well as the usual additives such as binding agents andflavorings.

For intestinal disinfection and for the oral treatment of infections ofthe urinal tract, in particular solid dosage unit forms such as tablets,dragees and capsules are suitable, which preferably contain between and90 percent of a diphenyl carbamic acid ester of Formula I to enable theadministration of daly doses of between 0.1 and 2.5 g to adults or ofsuitably reduced doses to children.

Tablets and dragee cores are produced by combining the carbamic acidesters of Formula I with solid, pulverulent carriers such as lactose,saccharose, sorbitol, maize starch, potato starch or amylopectin,cellulose derivatives or gelatin, preferably with the addition oflubricants such as magnesium or calcium stearate or polyethylene glycolsof suitable molecular weight. Dragee cores are then coated, for example,with concentrated sugar solutions which may also contain e.g., gumarabic, talcum and/or titanium dioxide, or they are coated with alacquer dissolved in volatile organic solvents or mixture of solvents.Dye-stuffs can be added to these coatings, e.g., to differentiatebetween varying dosages. Perles (pearl-shaped, sealed gelatine capsules)and other closed capsules consist, for example, of a mixture of gelatinand glycerin, and contain, e.g, mixtures of a new carbamic acid ester ofFormula I with polyethylene glycol. Hard gelatine capsules contain, forexample, granulates of an active substance with solid pulverluentcarriers such as, e.g., lactose, saccharose, sorbitol, mannitol;starches such as potato starch, maize starch or amylopectin, cellulosederivatives or gelatin, as well as magnesium stearate or stearic acid.

In all of the forms of administration, whether for technical, cosmetic,hygienic or medical use, the new diphenyl carbamic acid esters ofFormula I can be present as sole active ingredient or they can becombined with other known antimicrobial, in particular antibacterialand/or antimycotic substances, for example to broaden the range ofapplication. They can be combined, for example, with halogenatedsalicyclic acid alkyl amides and anilides, with halogenated diphenylureas, with halogenated benzoxazoles or benzoxazolones, withpolychlorohydroxy-diphenylmethanes, with halogen-dihydroxy-diphenylsulfides, with bactericidal 2-imino-imidazolidines or-tetrahydropyrimidines or with bactericidal quaternary compounds or withcertain dithiocarbamic acid derivatives such as tetramethylthiuramdisulfide. Optionally, carriers having themselves favorablepharmacological properties may also be used, such as sulfur as a powderbase, or zinc stearate as a component of ointment bases.

which has been melted at a moderate temperature. The mixture 1S allowedto cool while stirring.

EXAMPLE 6 dried. A sieved mixture of 3.0 g of highly dispersed si- 1nthe following examples, a number of typical forms of application forvarious uses are described.

EXAMPLE 4 Wound dusting powder: 3.00 g of active substance,

EXAMPLE 5 Antiseptic ointment: 3.0 g of active ingredient are trituratedwith 3.0 g of paraffin oil, and added to a mixr of g 9f. W99 fatandBt-.aq w itsv as net licic acid, 4.0 g of magnesium stearate, 0.7 g offlavoring and 42.3 of talcum is added to the dry granulate andthoroughly mixed. The mixture is pressed into 1,000 tablets.

EXAMPLE 7 Gargle concentrate: 5.0 g of active substance are dissolved in60.0 g of 96 percent ethanol, 15.0 g of glycerin and 0.3 g of flavoringare added and the solution is made up to 100.0 g with 19.7 g ofdistilled water. For

gargling, about 5 20 drops of this concentrate are used in water.

EXAMPLE 8 Tablets for the disinfection of the intestines and the urinaltract: To prepare 1,000 tablets each containing 150 mg of activesubstance, first 150.0 g of active substance are thoroughly mixed with60.0 g of maize starch and 35.0 g of lactose, and the mixture is evenlymoistened with a granulating solution prepared from 5.0 g of gelatin and3.0 g of glycerin in about g of water. The mass is granulated through asuitable sieve and dried. The granulate is thoroughly mixed with asieved mixture of 15.0 g of talcum, 10.0 g of dried maize starch and 2.0g of magnesium stearate. The mixture is pressed into 1,000 tablets.

EXAMPLE 9 Dragees for the disinfection of the intestines and the urinaltract: To prepare 1,000 dragee cores, first 150.0 g of active substanceare thoroughly mixed with 60.0 g of maize starch and 34.0 g of lactose.This mixture is mixed with a binding agent consisting of 6.0 g ofstarch, 3.0 g of glycerin and about 54 g of distilled water, and themass obtained is granulated through a suitable sieve and dried. Thegranulate is thoroughly mixed with a sieved mixture of 15.0 g of talcum,10.0 g of maize starch and 2.0 g of magnesium stearate, and the mixtureis pressed into 1000 dragee cores each weighing 280 mg.

The above cores are coated in a coating pan with a layer consisting of:2.000 g of shellac, 7.500 g of gum arabic, 0.180 g of dyestuff, 2.000 gof highly dispersed silicic acid, 35.00 g of talcum and 58.320 g ofsugar.

1000 dragees are obtained each weighing 385 mg and containing mg ofactive substance.

We claim:

1. A composition for controlling bacteria and fungi and for protectingorganic material against attack by bacteria and fungi which comprises(1) a bactericidally or fungicidially effective amount of anO,N-diphenylcarbamic acid ester of the formula R3 R4 R5 l l J. Q-

R! Br E9 wherein R represents phenoxy substituted by from 1 to 3identical or different halogen atoms selected from the group consistingof fluorine, chlorine and bromine,

one of R R and R represents chlorine or bromine, and each of the othersof R R and R represents hydrogen, chlorine or bromine,

each of R and R represents hydrogen, fluorine, chlorine, bromine, loweralkyl, lower alkoxy, halogeno-lower alkyl, nitro or hydroxy,

R represents hydrogen, fluorine, chlorine, bromine, lower alkyl, loweralkoxy, di-lower alkylamino or hydroxy, and W X represents oxygen orsulfur and (2) a carrier compatible with said ester.

2. The composition according to claim 1 wherein saidQN-diphenyl-carbamic acid ester is N-(3,5-dimethylphenyl)-carbamicacid-O-[2-(2,4'-dichlorophenoxy)- 5-chlorophenyl1-ester.

3. The composition according to claim 1, wherein saidO,N-diphenyl-carbamic acid ester is N-(3- methylphenyl)-thiocarbamicacid-O-[2-(2,4- dichlorophenoxy)-5-chlorophenyl]-ester.

4. The composition according to claim 1, wherein saidO,N-diphenyl-carbamic acid ester is N-(3-,

trifluoromethyl-4-chlorophenyl)-thiocarbamic acid-O- [2-( 4-chlorophenoxy )-5 -chlorophenyl ]-este r.

5. The composition according to claim 1, wherein saidO,N-diphenyl-carbamic acid ester is N-(4-methylphenyl)-carbamicacid-(H2-(4-chlorophenoxy)-4- bromo-S-chlorophenyl]-ester.

6. The composition according to claim 1, wherein said O,N -diphenylcarbamic acid ester is N-(3,4-

dichlorophenyl)-carbamic acid-O-[2-(2,4'-dichlorophenoxy)-5-chlorophenyl]-ester.

7. The composition according to claim 1, wherein said O,N-dipheny1carbamic acid ester is N-(3-nitro-4- chlorophenyl)-carbamicdichlorophenoxy)-5-chlorophenyl]-ester.

8. The composition according to claim 1, wherein said O,N-diphenylcarbamic acid ester is N-(3- trifluoromethylphenyl)-carbamicdichlorophenoxy)-5-chlorophenyl]-ester.

9. The composition according to claim 1, wherein said O,N-diphenylcarbamic acid ester is N-(4-hydroxyphenyl)-carbamicacid-O-[2-(2',4'-dichlorophenoxy)- 5-chlorophenyl]-ester.

10. The composition according to claim 1, wherein said O,N-diphenylcarbamic acid ester is N-(4- methylphenyl)-thiocarbamic acid-O-[2-(2,4-dichlorophenoxy)-5-chlorophenyl]-ester.

11. The composition according to claim 1, wherein said QN-diphenylcarbamic acid ester is N-(3- methylphenyl)-thiocarbamic acid-O-[2-(2,4-dichlorophenoxy)-5-chloropheny1]-ester. I

12. The composition according to claim 1, wherein said O,N-diphenylcarbamic acid ester is N-(Z-methylphenyl)-carbamicacid-O-[2-(2,4-dichlorophenoxy)- 4bromo-5-chlorophenyl]-ester.

13. A method for controlling bacteria and fungi and for protectingorganic materials against attack by bacteria and fungi, which comprisesapplying to an area infested by said bacteria or.fungi or to an organicmaterial to be protected against said bacteria and fungi abacteriacidally or fungicidally effective amount of a compound of theformula wherein R represents phenoxy substituted by from 1 to 3identical or different halogen atoms selected from the group consistingof fluorine, chlorine and bromine,

one of R R and R represents chlorine or bromine, and each of the othersof R R and R represents hydrogen, chlorine or bromine,

each of R and R represents hydrogen, fluorine, chlorine, bromine, loweralkyl, lower alkoxy, halogeno-lower alkyl, nitro or hydroxy,

R represents hydrogen, fluorine, chlorine, bromine, lower alkyl, loweralkoxy, di-lower alkylamino or hydroxy, and

X represents oxygen or sulfur.

14. The method according to claim 13 in which the compound isN-(Z-methylphenyl)-thiocarbamic acid-O-[2-(2,4-dichlorophenoxy)-5-chlorophenyl]-ester.

15. The method according to claim 13 in which the compound isN-(3-trifluoromethyl-4-chlorophenyl)- thiocarbamicacid-O-[2-(4-chlorophenoxy)-5- chlorophenyl]-ester.

16. The method according to claim 13 in which the compound isN-(4-methylphenyl)-carbamic acid-O-[2-(4-chlorophenoxy)-4-bromo-5-chlorophenyl] ester.

17. The method according to claim 13 in which the compound isN-(3,4-dichlor0phenyl)-carbamic acid-O-[2-(2',4-dichlorophenoxy)-5-chlorophenyl]-ester.

18. The method according to claim 13 in which the compound isN-3-nitro-4-chlorophenyl)-carbamicacid-O-[2-(2',4-dichlorophenoxy)-5-chlorophenyl]- ester.

19. The method according to claim 13 in which the compound isN-(3-trifluoromethylphenyl)-carbamicacid-O-[2-(2',4'-dich1orophenoxy)-5-chlorophenyl]- ester.

20. The method according to claim 13 in which the compound isN-(4-hydroxyphenyl)-carbamic acid-O-[2-(2',4'-dichlorophenoxy)-5-chlorophenyl]-ester.

21. The method according to claim 13 in which the compound isN-4-methylphenyl)-thiocarbamic acid-O-[2-(2',4-dichlorophenoxy)-5-chlorophenyl]-ester.

22. The method according to claim 13 in which the compound isN-(3-methylphenyl)-thiocarbamic acid-O-[2-(2',4'-dichlorophenoxy)-5-chlorophenyl]-ester.

23. The method according to claim 13 in which the compound isN-(Z-methylphenyl)-carbamic acid-O-[ 2-(2,4-dichlorophenoxy)-4-bromo-5-chlorophenyl]- ester.

1. A COMPOSITION FOR CONTROLLING BACTERIA AND FUNGI AND FOR PROTECTINGORGANIC MATERIAL AGAINST ATTACK BY BACTERIA AND FUNGI WHICH COMPRISES(1) A BACTERICALLY OR FUNGICIDIALLY EFFECTIVE AMOUNT OF ANO,N-DIPHENYLCARBAMIC ACID ESTER OF THE FORMULA
 2. The compositionaccording to claim 1 wherein said O,N-diphenyl-carbamic acid ester isN-(3,5-dimethylphenyl)-carbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 3. Thecomposition according to claim 1, wherein said O,N-diphenyl-carbamicacid ester is N-(3-methylphenyl)-thiocarbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 4. Thecomposition according to claim 1, wherein said O,N-diphenyl-carbamicacid ester is N-(3-trifluoromethyl-4-chlorophenyl)-thiocarbamicacid-O-(2-(4''-chlorophenoxy)-5-chlorophenyl)-ester.
 5. The compositionaccording to claim 1, wherein said O,N-diphenyl-carbamic acid ester isN-(4-methylphenyl)-carbamicacid-O-(2-(4''-chlorophenoxy)-4-bromo-5-chlorophenyl)-ester.
 6. Thecomposition according to claim 1, wherein said O,N-diphenyl carbamicacid ester is N-(3,4-dichlorophenyl)-carbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 7. Thecomposition according to claim 1, wherein said O,N-diphenyl carbamicacid ester is N-(3-nitro-4-chlorophenyl)-carbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 8. Thecomposition according to claim 1, wherein said O,N-diphenyl carbamicacid ester is N-(3-trifluoromethylphenyl)-carbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 9. Thecomposition according to claim 1, wherein said O,N-diphenyl carbamicacid ester is N-(4-hydroxyphenyl)-carbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 10. Thecomposition according to claim 1, wherein said O,N-diphenyl carbamicacid ester is N-(4-methylphenyl)-thiocarbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 11. Thecomposition according to claim 1, wherein said O,N-diphenyl carbamicacid ester is N-(3-methylphenyl)-thiocarbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 12. Thecomposition according to claim 1, wherein said O,N-diphenyl carbamicacid ester is N-(2-methylphenyl)-carbamicacid-O-(2-(2'',4''-dichlorophenoxy)-4-bromo-5-chlorophenyl)-ester.
 13. Amethod for controlling bacteria and fungi and for protecting organicmaterials against attack by bacteria and fungi, which comprises applyingto an area infested by said bacteria or fungi or to an organic materialto be protected against said bacteria and fungi a bacteriacidally orfungicidally effective amount of a compound of the formula
 14. Themethod according to claim 13 in which the compound isN-(2-methylphenyl)-thiocarbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-CHLOROPHENYL)-ester.
 15. Themethod according to claim 13 in which the compound isN-(3-trifluoromethyl-4-chlorophenyl)-thiocarbamicacid-O-(2-(4''-chlorophenoxy)-5-chlorophenyl)-ester.
 16. The methodaccording to claim 13 in which the compound isN-(4-methylphenyl)-carbamicacid-O-(2-(4''-chlorophenoxy)-4-bromo-5-chlorophenyl)-ester.
 17. Themethod according to claim 13 in which the compound isN-(3,4-dichlorophenyl)-carbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 18. Themethod according to claim 13 in which the compound isN-3-nitro-4-chlorophenyl)-carbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 19. Themethod according to claim 13 in which the compound isN-(3-trifluoromethylphenyl)-carbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 20. Themethod according to claim 13 in which the compound isN-(4-hydroxyphenyl)-carbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 21. Themethod according to claim 13 in which the compound isN-4-methylphenyl)-thiocarbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 22. Themethod according to claim 13 in which the compound isN-(3-methylphenyl)-thiocarbamicacid-O-(2-(2'',4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 23. Themethod according to claim 13 in which the compound isN-(2-methylphenyl)-carbamicacid-O-(2-(2'',4''-dichlorophenoxy)-4-bromo-5-chlorophenyl)-ester.